RNA folding in the living cell: Group II introns and their intracellular structure
(START Prize Y401)

Despite RNA’s importance for cell viability little is known about how RNA folds in vivo and how they interact with their targets. Therefore, it is of fundamental importance to gain insights into the forces driving RNA folding in vivo and to establish the contribution and impact of the cellular environment, in order to understand the basic mechanism of these RNA-dependent processes. Catalytic RNAs, in particular group II introns, are the best-suited model system to study RNA folding in the living cell, as their structure and folding pathways are well characterized in vitro and formation of the native conformation can be measured as a function of catalysis. Therefore, we investigate the intracellular folding pathway of the Sc. ai5γ group II intron. Importantly, Sc. ai5γand other yeast mitochondrial introns depend on trans-acting protein factors for efficient splicing in vivo. Consequently, we are interested in exploring how these proteins shape folding of its target RNAs. This allows us to derive principles governing in vivo RNA folding facilitated by proteins and other cellular factors.

Telomerase: RNA-protein interactions and RNP assembly
Telomerase is a large ribonucleoprotein complex that plays a major role in the maintenance of telomeres, which form a protective cap of chromosome ends. Telomerases from all species contain an essential RNA component (TER), a unique reverse transcriptase protein (TERT) and several accessory proteins involved in assembly, accumulation and localization. TERT uses the intrinsic RNA as template for the extension of the telomere, whereby shortening of telomeres below a critical length leads to cell aging. Telomerase has received considerable attention because of its significant up-regulation in the majority (>90%) of cancer cells and its role in preventing chromosomal instability and senescence. In addition, mutations in both TER and the telomerase accessory protein dyskerin have been linked to the inherited human disorders, Dyskeratosis Congenita and Aplastic Anemia. In spite of the high level of interest in the biological and medical importance of telomerase, telomerase RNA and protein components have largely eluded structural characterization. In this regard, we are interested in exploring the structure of telomerase RNA and in studying the interplay of RNA folding and RNP assembly.